Lapatinib is a pharmaceutically active ingredient used for the treatment of advanced metastatic lung cancer and is currently available on the market under the name Tykerb® sold by GlaxoSmithKline (GSK).
According to the indications of the manufacturer, Tykerb® contains Lapatinib as a monohydrate ditosylate salt of formula (XIII-bis):
having the chemical name of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)furan-2-yl]quinazoline-4-amine bis(4-methylbenzenesulfonate) monohydrate, CAS RN 388082-78-8 and melting point 250-256° C.
This substance may be prepared using methods described for example in U.S. Pat. No. 7,157,466. Examples 10 and 11 of this reference show the preparation of monohydrate ditosylate salt starting from anhydrous ditosylate salt.
Like other compounds obtained by means of chemical synthesis, Lapatinib, or salts thereof, may contain small amounts of impurities. These impurities may be raw materials, synthetic intermediaries, reaction by-products, product degradation products, and the like. Pharmaceutical impurities, may affect both the efficiency and the safety of a drug which, in extreme cases, could be harmful for the patient. The purity of an active ingredient like Lapatinib produced through a production process based on subsequent chemical reactions represents a critical factor with respect to commercialization. The United States Food and Drug Administration (FDA) and the European Medicinal Agency (EMA) (as well as their respective pharmacopoeia) require that impurities be maintained below given limits.
The product of a chemical reaction rarely involves a single compound having purity sufficient to meet regulatory standards. By-products due to secondary reactions of reagents also can be present in the isolated product. In certain steps of the production process of an active ingredient, such as Lapatinib, the purity may be analysed, generally by methods such as high performance liquid chromatography (HPLC), gas chromatography (GC) or thin layer chromatography (TLC), to determine whether the active ingredient is suitable for subsequent treatment and for use in the final pharmaceutical product. Generally, impurities are identified spectroscopically and provide a chromatographic peak on a chromatogram or as a spot on a TLC panel.
Once a peak position has been associated with a particular impurity, the impurity can be identified in a sample based on its position in the chromatogram, where the position in the chromatogram is measured in minutes between the injection of the sample in a column and elution of the impurity through the detector. The position in the chromatogram is known as the retention time and the ratio between the retention times is known as the relative retention time.
A relatively pure compound may be used as a reference standard. A reference standard is similar to a reference marker, except that the latter can be used not only for detecting impurities, but also for quantifying the amount of impurities present in the sample.
Impurities of Lapatinib, including intermediaries not entirely reacted, impurities of the raw materials, the reaction by-products, degradation products, as well as other products, may affect the quality and efficiency of the pharmaceutical form containing Lapatinib. Thus, there is a great need for methods of defining the level of impurities in samples of Lapatinib and methods for removing impurities, limiting the content thereof or preventing the formation thereof.